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01/12/2016 Endocrinology and Reproduction Elisabet Stener-Victorin Associate professor Department of Physiology and Pharmacology Group: Reproductive Endocrinology and Metabolism General Consepts of Endocrine Control Hormone – Greek hormaein = ”excite” Hormones are produced by glands and other cells Hormones – Chemical substances that are secreted from endocrine cells to exert an effect on other cells in the body´and coordinate biological function Transported in the blood or via tissue fluid and reach almost all cells in the body General Potential to affect all cells in the body Selective Affect cells in specific target organs, i.e. Cells with hormon receptors 1 01/12/2016 General Consepts of Endocrine Control Autocrine signalling = regulate the same cell as secreted the substance Paracrine signalling = via extra cellular fluid to target cells Endocrine signalling = via blood to target cells Classical Endocrine Organs Other ”non-classical” hormone producing glands e.g. CNS Kidney Stomach Small intestine Skin Heart Lung Placenta Katch et al Essentials of Exercise Physiol. Figure 12.1 2 01/12/2016 Hormones Controls and Regulates Reproduction including gamete production, fertilization, nourishment of the embryo and fetus Growth and development Regulates ion and water balance Regulates cellular metabolism and energy balance Mobilize the immun system by responding to infection, trauma, and emotional stress Homeostasis Maintance of steady states by coordinated physiological mechanisms during rest and activity The endocrine system contributes to homeostasis by controlling availablity of substrates and metabolism By regulating body fluid and ion balance Homeostasis – like thermostat in the room Body temperature ~ 37ºC Blood glucose 4.4 – 6.1 mM Ca2+ 4.1 – 5.2 mg/dL Phosphate 0.8 – 1.5 mM Iron 65 – 176 µg/dL 3 01/12/2016 How is homestasis achived? Three components in the endocrine system: 1. Gland 2. Hormone 3. Target organ Homeostasis 1. Hormone 2. Receptor 3. Response Katch et al Essentials of Exercise Physiol. Figure 12.2 Principles for Feed-back Positive (rare) Negative Endocrine cell Endocrine cell A A Complex multilevel Hypothalamus Releasing hormone Anterior pituitary Target Endocrine cell Target Endocrine cell B B Biological effect Biological effect Target hormone Target Endocrine cell Endocrine cell hormone Biological effect 4 01/12/2016 Principles for Feed-back and Biorythm Long feedback loop Active hormone regulates the hypothalamus Short feedback loop Active hormone regulates pituitary Ultrashort feedback loop Pituitary hormones regulate the release from hypothalamus via portal blood flow Complex multilevel Hypothalamus Releasing hormone Anterior pituitary Target hormone Biorytm - Pulsatile release Circadian rythm (cortisol) Monthly rythm (female sex hormones) Life rythm (growth hormone) Target Endocrine cell Endocrine cell hormone Biological effect What regulates the hormone production and secretion? Hormone secretion is mainly regulated by feed-back loops Cause changes in the body Low circulating/tissue levels secretion High circulating/tissue levels secretion Like the thermostat at home Hormone sensitivity and responsiveness Synergism e.g. estrogen – progesterone – prolactin – synergism in milk secretion Antagonism e.g. insulin decrease and glucagon increase glucose Permissiveness e.g. cortisol on catecholamine's 5 01/12/2016 Hypothalamus –”the boss” functional connections Fysiologi, Lännergren, Westerblad, Ulfendahl, Lundeberg och Studentlitteratur 2012 Fig. 4.4 Principle mechanisms of hormonal transport and bioavailability Circulating hormone concentration → synthesis and secretion Protein binding Many hormone are bound to and transported with plasma proteins (e.g. albumin) → only free hormones can exert and effect, be eliminated, and exert feed back regulation Local enzymes in the tissue Activates e.g. testosterone to more potent forms DHT Inactiviates of e.g. cortisol in the kidney Pulsatility Some hormones are released to a higher/lower degree during specific time points e.g. cortisol, GH, LH/FSH Type of receptors There can be different types of receptors to the same hormone in the tissue Different effect of the hormone depending on which receptor that is activated 6 01/12/2016 Different hormones classes - types Three main types: 1. Amines - Tyrosine derivatives 2. Peptides 3. Steroids 4. (Lipid hormones) Different types of hormones → different prerequisite mechanisms → different effects e.g.: Hydrophobic vs hydrophilic Pass the cell membrane Free vs bound in the blood Bind on the surface or inside the cell Do they change ”signals” or do they change the number or proteins Elisabet Stener-Victorin 13 Hormone classes 1 1. Amine hormones Derives from one or two amino acids Water soluble Eg. Norepinephrine, thyroid hormones Bind to G-coupled membrane receptors When bound to their receptor, they activate a cascade of intracellular signaling molecules called second messengers 7 01/12/2016 Hormone classes 2 2. Peptide-derived hormones Peptides = Proteins e.g. insulin and glucagon → synthesized by ribosomes as prohormones Water soluble, most circulated freely and are membrane impermeable Bind to G-protein coupling receptors and exert their effect by modulating second messengers Water soluble hormones Amines Thyroid hormones (T3, T4) → Like steroid-hormones Catecholamine's (adrenalin, norepinephrine) → Short half-time, receptor localized in the cell membrane, activates second messengers and modifies already existing proteins Protein/peptid hormones – from several amino acids Pancreas (insulin, glucagon), hypothalamus (GnRH), hypofys (FSH, LH) → Short half-time, receptor localized in the cell membrane, activates second messengers and modifies already existing proteins, AND induce protein synthesis 8 01/12/2016 How does water soluble hormones exert their effects? 1 Hormone (1st messenger) binds receptor. Extracellular fluid Adenylate cyclase G protein (GS) 5 cAMP activates protein kinases. Receptor GDP 2 Receptor activates G protein (GS). Hormones that act via cAMP mechanisms: Epinephrine ACTH FSH LH 3 G protein activates adenylate cyclase. Glucagon PTH TSH Calcitonin 4 Adenylate cyclase converts ATP to cAMP (2nd messenger). Active protein kinase Inactive protein kinase Triggers responses of target cell (activates enzymes, stimulates cellular secretion, opens ion channel, etc.) Cytoplasm Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.2 Hormone Class 3 - Steroid hormones All derives from cholesterol Hyodrophobic, membrane permeable, and change protein expression Hydrophobic = protein bound Slower effect and more long lasting effects Two main types of receptors: Steroid receptors bind to receptor in cytosol and translocate to the nucleus Thyroid receptors bind to the receptor directly in the nucleus 9 01/12/2016 Steroid and thyroid hormone transport Approx 90% of steroid and thyroid hormones in the blood are bound to plasma proteins Only the free hormone that is biological active Free hormone and carrier-bound hormone – dynamic equilibrium Transport protein Principle hormone(s) transported Specific Corticosteroid-binding protein (transcortin) Cortisol, aldosterone Thyroxid-binding globulin Thyroxin, triiodothyronine Sex hormone-binding globulin Testosterone, estrogen Nonspecific Serum albumin Most steroids, thyroxin, triiodothyronine Transthyretin (prealbumin) Thyroxin, some steroids Elisabet Stener-Victorin 01/12/2016 19 How does steroid hormones exert its effect? Receptors located in cytoplasm Hormone–receptor complex enters the nucleus Binds to DNA, direct gene activation/inhibition by transcription and translation Regulates mRNA synthesis and protein synthesis Steroid hormones produced and secreted from 4 main organs Adrenal cortex (cort, aldost) Ovaries (E2 and T) Testicles (T) Placenta (E2, PR) Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 4.2 © 2013 Pearson Education, Inc. 10 01/12/2016 Cells can regulate their receptor number and/or function in several ways Hormone excess → ↓ number of receptors for that hormone per cell i.e. down-regulation Lack of hormone → ↑ number of receptors i.e. up-regulation Chronic exposure of cells to a hormone may cause desensitization Hormone response – what more regulates it? Rate of production → stored or synthezised? Bound or free state Rate of degradation Hypothalamus – “the boss” Elisabet Stener-Victorin 01/12/2016 22 11 01/12/2016 Hypothalamus Hypothalamus Part of the limbic system Control hormonal release from pituitary Neuroendocrine and endocrine control: Posterior pituitary (neuro): Efferent nerves secreting hormones Anterior pituitary (adeno): Portal system secreting many hormones Elisabet Stener-Victorin 01/12/2016 23 Hypothalamus Regulates basal body functions: Biorhythms (suprachiasmatic nucleus) Body temperature Sleep Defense – alarm – fear – aggressively Growth Reproduction and behavior Delivery Thirst (osmoreceptors) Urine (osmoreceptors and antidiuretic hormone, ADH) Appetite – target organ for leptin Basal metabolic activity (thyroid releasing hormone) 12 01/12/2016 Pituitary Gland Elisabet Stener-Victorin 01/12/2016 25 Posterior Pituitary (neurohypophysis) Oxytocin → synthesized in paraventricular nucleus Stimulates milk secretion Stimulates uterine contractions during delivery Arginine vasopressin = antidiurethic hormone (ADH) → synthesized in supratoptic nucleus Regulates blood volume ADH secretion regulated by hypothalamic osmorecetors Main effect of ADH – decrease water excretion and increase water absorption in the kidney Källa: Netter. Atlas of Human Anatomy. Ciba-Geigy 1989 13 01/12/2016 Anterior pituitary - adenohypophysis Hypothalamic neurons synthesize GHRH, GHIH, TRH, CRH, GnRH, PIH. Hypothalamus Anterior lobe of pituitary Superior hypophyseal artery 2 Releasing hormone stimulate or inhibit release of hormones made in the anterior pituitary 3 In response to releasing hormones, the anterior pituitary secretes GH, TSH, ACTH, FSH, LH, PRL Anterior lobe of pituitary 1 Hypothalamic neurons secrete releasing or inhibiting hormones into the portal plexus Hypophyseal portal system A portal • Primary capillary plexus system is • Hypophyseal two portal veins capillary • Secondary plexuses capillary plexus (beds) connected by veins. Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.4c © 2013 Pearson Education, Inc. Anterior pituitary - adenohypophysis Katch et al Essentials of Exercise Physiol. Figure 12.4 14 01/12/2016 Hormone release and homeostasis Hypothalamus Pituitary Growth hormone Thyroid Adrenal gland Pancreas Gonades (ovary/testis) Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Regulation of anterior pituitary hormones Källa: Endokrinologi. Werner 2004 15 01/12/2016 Growth Hormone (GH) → IGF-1 GH stimulates body growth Important for normal body development Metabolic effects Protein synthesis → increase amino acid transport into cells, enhance DNA and RNA transcription, RNA translation of protein and decrease protein and amino acid catabolism Increase blood glucose → Glycogenolys (glucose production by breakdown of glycogen) in the liver, increased gluconeogenesis and insulin production (similar to type 2 diabetes) Decrease glucose uptake in muscle and adipose tissue Lipolysis (break down of fat cells) → increase concentrations of fatty acids Growth Hormone axis GH has a pulsatile secretion pattern Maximal secretion during the first hours of sleep GH highest in adoloscents (peaking late puberty) Adulthood - decreased size of the pulsatile burst, no change in number of pulses 16 01/12/2016 Growth Hormone Regulation Inhibits GHRH release Stimulates GHIH release Inhibits GH synthesis and release Feedback Anterior pituitary Hypothalamus secretes growth hormone—releasing hormone (GHRH), and somatostatin (GHIH) Growth hormone Direct actions (metabolic, anti-insulin) Indirect actions (growthpromoting) Liver and other tissues Produce Insulin-like growth factors (IGFs) Effects Effects Skeletal Fat Carbohydrate metabolism Increased fat breakdown and release Increased blood glucose and other anti-insulin effects Extraskeletal Increased cartilage Increased protein synthesis, and formation and cell growth and skeletal growth proliferation Increases, stimulates Reduces, inhibits Initial stimulus Physiological response Result Hormone release and homeostasis Hypothalamus Pituitary Growth hormone Thyroid Adrenal gland Pancreas Gonades (ovary/testis) Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 17 01/12/2016 Thyroid Hormone (TH) Two related compounds T4 (thyroxine); has 2 tyrosine molecules + 4 bound iodine atoms T3 (triiodothyronine); has 2 tyrosines + 3 bound iodine atoms Major metabolic hormone – set basal metabolic rate Increases metabolic rate and heat production ↑ Mitochondria ↑ blood flow, heart rate, and cardiac output ↑ Respiration ↑ Expression of NA+/K+ ATPase → ↑ neural signaling → muscle tremor (hyperthyroidism) Plays a role in: Maintenance of blood pressure Regulation of tissue growth Development of skeletal and nervous systems Reproductive capabilities Control of Thyroid Function Action of Thyroid hormones Metabolic Actions Permissive Actions – on catecholamine's by increasing synthesis of β-adrenergic receptors Growth and Development Basal metabolism Carbohydrate metabolism Protein metabolism Lipid metabolism Thermogenes 1. 2. Low thyroid hormones Gluconeogenesis Glycogenolys Synthesis Proteolysis Lipogenes Lipolys Serum cholesterol High thyroid hormones Gluconeogenesis Glycogenolys Synthesis Proteolysis Lipogenes Lipolys Serum cholesterol Glycogenolys = breakdown of glycogen Gluconeogenesis = generation of glucose from substrates like pyrovate, lactate, glycerol and glucogenic amino acids 36 18 01/12/2016 Parathyroid Glands and Parathyroid Hormone Four tiny glands embedded in the posterior aspect of the thyroid Contain cells that secrete parathyroid hormone (PTH) PTH—most important hormone in the calcium (Ca2+) homeostasis Calcium function – Necessary for: Structural: Bone, teeth, connective tissue Muscle contraction Blood clotting Nerve impulse transmission and stability of excitable membranes Enzyme activity Calcium homeostasis Hypocalcemia (low blood Ca2+) stimulates parathyroid glands to release PTH. Rising Ca2+ in blood inhibits PTH release. Bone 1 PTH activates osteoclasts: Ca2+ released into blood. Kidney Ca2+ reabsorption in kidney tubules. 3 PTH promotes kidney’s activation of vitamin D, which increases Ca2+ absorption from food. 2 PTH increases PTH primary physiological effect is to decrease calcium It´s main effect in the Bone: Stimulates net resorption →↑ Ca2+ in the blood Kidney: Increase Ca2+ reabsorption, inhibits reabsorption of phosphate and promotes kidney activation of vitamin D Intestine Ca2+ ions PTH Molecules Bloodstream 19 01/12/2016 Hormone release and homeostasis Hypothalamus Pituitary Growth hormone Thyroid Adrenal gland Pancreas Gonades (ovary/testis) Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Regulation of anterior pituitary hormones Källa: Endokrinologi. Werner 2004 20 01/12/2016 Adrenal Gland Hormones 41 Hypothalamus-Pituitary-Adrenal (HPA) axis Hypothalamus - Pituitary Corticotropin Releasing Hormone (CRH) from hypothalamus stimulates Adrenocorticotropic hormone (ACTH) from adenohypophysis which stimulates Adrenal cortex to stimulates three different steroid hormones: Mineralcorticoids - aldosteron Glucocortoids - cortisol Sex steroids – androgens and estrogens Lännergren J, Westerblad H, Ulfendahl M, Lundeberg T och Studentlitteratur 2012 Fig 15.8 21 01/12/2016 Regulation of aldosterone Primary regulators ↓Blood volume and/or blood pressure Other factors ↑ K+ in blood Stress ↑ Blood pressure and/or blood volume Hypothalamus Kidney Renin Initiates cascade that produces Heart CRH Anterior pituitary Direct stimulating effect ACTH Angiotensin II Atrial natriuretic peptide (ANP) Inhibitory effect Zona glomerulosa of adrenal cortex Enhanced secretion of aldosterone Targets kidney tubules ↑ Absorption of Na+ and water; increased K+ excretion ↑ Blood volume and/or blood pressure HPA axis is regulated by stress and diurnal variation 22 01/12/2016 Cortisol – Diurnal Variation – Circadian Rhytm How to measure cortisol concentrations? Saliva 24 h urine Elisabet Stener-Victorin 01/12/2016 45 Glucocorticoids – cortisol – zona fasciculata Cortisol is the most significant glucocorticoid - Important for life Released in response to ACTH, patterns of eating and activity, and stress Metabolic effects Proteolysis, lipolysis, gluconeogenesis—formation of glucose from fats and proteins, promotes rises in blood glucose, fatty acids, and amino acids (insulin antagonist), increased hunger Cardiovascular effects (important for life) Permissive effect on α1-receptors → catecholamines can contract vessels CNS Memory, sensory integration, limbic system Bone and Connective tissue Stimulates bone resorption (decomposition), inhibits bone formation, inhibits K+ uptake in the intestine, increase K+ from the kidney Immune system Stimulates bone resorption (decompostion), inhibits bone formation, inhibits K+ uptake in the intestine, increase K+ from the kidney permissiveness is a biochemical phenomenon in which the presence of one hormone is required in order for another hormone to exert its full effects on a target cell 23 01/12/2016 Short-term stress More prolonged stress Stress Sympathetic -Adrenal (SA) axeln Nerve impulses HypothalamusPituitary-Adrenal (HPA) axis Hypothalamus CRH (corticotropinreleasing hormone) Spinal cord Corticotroph cells of anterior pituitary Preganglionic sympathetic fibers To target in blood Adrenal medulla (secretes amino acidbased hormones) Catecholamines (epinephrine and norepinephrine) Short-term stress response 1. Increased heart rate 2. Increased blood pressure 3. Liver converts glycogen to glucose and releases glucose to blood 4. Dilation of bronchioles 5. Changes in blood flow patterns leading to decreased digestive system activity and reduced urine output 6. Increased metabolic rate Adrenal cortex (secretes steroid hormones) ACTH Mineralocorticoids Glucocorticoids Long-term stress response 1. Retention of sodium and water by kidneys 2. Increased blood volume and blood pressure 1. Proteins and fats converted to glucose or broken down for energy 2. Increased blood glucose 3. Suppression of immune system Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.16 Gonadocorticoids (Sex Hormones) Most are androgens (male sex hormones) that are converted to testosterone in tissue cells or estrogens in females May contribute to The onset of puberty The appearance of secondary sex characteristics Sex drive In women – most important after menopause 24 01/12/2016 Hormone release and homeostasis Hypothalamus Pituitary Growth hormone Thyroid Adrenal gland Pancreas Gonades (testis/ovary) Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 Endocrine pancreas Exocrine Secretes bicarbonate ions and digestive enzymes Endocrine 1. -cells secrete glucagon and increase glucose release from the liver into the blood. Antagonistic effect to insulin. Pro-glucagon is also expressed in intestinal L cells → GLP-1 2. -cells secrete insulin, pro-insulin, C-peptide and amylin – decrease blood glucose 3. -cells secrete somatostatin – inhibits secretion of insulin and glucagon and inhibit GI-tract 4. F-cells secrete pancreatic poly peptide (PP) – inhibits gastric acid secretion 25 01/12/2016 Glucose homeostasis Glucose is the most important energy source in human (and most other lifeforms) Tight regulation under several hormones: GH Cortisol Adrenaline Insulin Glucagon Katch et al Essentials of Exercise Physiol. Figure 12.9 Insulin signalling and muscle contraction IR Glukos p -Tyr IRS-1 PI3-K Mitochondrial biogenesis Oxidative stress AS160 GLUT-4 Akt Muskel Contraction – insulin independent 26 01/12/2016 Insulin resistance Insulin Resistance Normal β-cell function Compensatory hyperinsulinemia Abnormal β-cell function Relative insulin deficiency Hyperglycemia Normoglycemia Type 2 diabetes Insulin resistance in peripheral target tissues Liver ↓Glycogen synthesis Muscle ↓GLUT4 transloc. ↓Glucose uptake ↓Glycogen synthesis ↓Glucose oxidation Liver Adipose tissue ↑Gluconogenesis ↑Lipogenesis ↑Lipolysis ↑TG ↑FFA 27 01/12/2016 Glucose metabolism Insulin need Insulin production Healthy (Normoglycemia) Type I diabetes (Hyperglycemia) IR (Normoglycemia) Type II diabetes (Hyperglycemia) Metabolic syndrome Dyslipidemia Elevated blood pressure Insulin resistance Glucose intolerance Abdominal obesity Increased risk of developing Cardiovascular Disease (CVD) 28 01/12/2016 Metabolic syndrome International Diabetes Federation (IDF) 2005 1. Visceral obesity: Waist 94 cm (men) and waist 80 cm (women) and at least 2 of the following: 2. High triglycerides: >1,7 mmol/L 3. Low HDL-cholesterol: < 1,03 mmol/L (men) <1,29 mmol/L (women) 4. Blood pressure 130/85 or medication 5. Fasting plasma glucose ≥5,6 mmol/L or diagnosed type 2 diabetes Hormone release and homeostasis Hypothalamus Pituitary Growth hormone Thyroid Adrenal gland Pancreas Gonades (testis/ovary) Marieb E, N., Hoehn, K. Human anatomy and Physiology Figure 16.1 29 01/12/2016 Regulation of anterior pituitary hormones Källa: Endokrinologi. Werner 2004 Circulating sex steroid hormone levels in men and women Estradiol - females Testosterone - male Estradiol - male Testosterone - females Ober et al 2008 Nat Rev Genet 30 01/12/2016 Male hormonal (androgenic) effects 1. Development – male sexual differentiation Puberty – secondary sexual changes and muscle/bone/voice/phallus(penis)/libido Post-puberty – prostate growth, muscle mass and sexual function 2. 3. Leonidas Lundell 6 december 2014 91 Regulation of sex steroids in men Androgenic effects in the body: Development of male genitalia Male pattern hair growth Growth of the larynx and vocal cords Sperm production Muscle growth Visceral fat accumulation Increased sexual drive and potens Aggressive behavior Leyding celler → produce testosteron ABP = androgen binding protein Marieb E, N., Hoehn, K. Human anatomy and Physiology Fig 27.10 31 01/12/2016 Tunica albuginea Degenerating corpus luteum (corpus albicans) Oocyte Cortex Granulosa cells Late secondary follicle Mesovarium and blood vessels Germinal epithelium Vesicular (Graafian) follicle Antrum Oocyte Primary follicles Ovarian ligament Zona pellucida Theca folliculi Ovulated oocyte Medulla Corpus luteum Developing corpus luteum Corona radiata Hypothalamus-Pituitary-Ovary axis (HPO) Källa: Human Anatomy & Physiology Av Elaine N. Marieb & Katja Hoehn Fig 27.21 32 01/12/2016 Menstrual cycle Pituitary hormones (blood) ”Ovary cycle” – follicle development Källa: Human Anatomy & Physiology Av Elaine N. Marieb & Katja Hoehn Fig 27.22 Ovary hormone (blood) Endometrium [email protected] 33 01/12/2016 Endocrinology and Reproduction Part 2 Elisabet Stener-Victorin Associate professor Department of Physiology and Pharmacology Group: Reproductive Endocrinology and Metabolism Describe the pathophysiology (cause and symptoms) of the following endocrine disorders: Dwarfism, gigantism, acromegaly Cretinism Goiter Hyperthyroidism Hypothyroidism Osteoporosis Cushings syndrome and Cushings disorder Type 1 diabetes and Type 2 diabetes Polycystic Ovary Syndrome Hypothalamic insufficiency Elisabet Stener-Victorin 01/12/2016 68 34